One goal of this study is to test the hypothesis that insulin resistance is a basic defect in patients with non-insulin dependent diabetes mellitus (NIDDM), and has a genetic basis. Consequently, we will quantitate insulin action (insulin-stimulated glucose disposal by the glucose clamp technique) and insulin secretion {insulin release in response to intravenous and oral glucose and a mixed liquid meal) in four well-defined groups of individuals and their first-degree relatives. These four groups will consist of: 1) relatively insulin sensitive nondiabetic subjects; 2) relatively insulin resistant nondiabetic subjects; 3) insulin resistant patients with glucose intolerance in the absence of fasting hyperglycemia; and 4) patients with NIDDM and significant fasting hyperglycemia. A second goal is to use these four index populations and their family members for collaborative studies with the other four investigators in an effort to define the pathogenesis of the observed changes in insulin secretion and action. These experiments will involve the following: 1) Use of freshly isolated monocytes, adipocytes, and cultured lymphocytes to study both insulin receptor dynamics, biosynthesis, and kinase activity, and insulin action on biological functions (Dr. Goldfine); 2) Restriction fragment length polymorphism analysis to probe the genes for insulin, insulin like growth factors, insulin receptor and the glucose transporter (Dr. Karam; 3) Measurements of plasma cholecystokinin and the definition of its relationship to the insulin secretory response of the various population groups (Dr. Liddle); 4) Exploration of the role of glucose-induced desensitization in the defects of insulin secretion in patients with NIDDM (Dr. Grodsky); and 5) Whether, circulating peptides present in plasma extracts can regulate insulin release from perfused rat islets, and whether these peptides are altered in NIDDM (Dr. Grodsky).